Arthritis Research & Therapy
Vol 6 Suppl 2 Yocum
Review
Effective use of TNF antagonists
David Yocum
University of Arizona Arthritis Center, Tucson, AZ, USA
Corresponding author: David Yocum (e-mail: yocum@u.arizona.edu)
Received: 17 Jul 2003
Accepted: 6 Aug 2003
Published: 21 Jun 2004
Arthritis Res Ther 2004, 6(Suppl 2):S24-S30 (DOI 10.1186/ar997) © 2004 BioMed
Central Ltd (Print ISSN 1478-6354; Online ISSN 1478-6362)
Abstract
Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes
in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to
develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the
use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment,
combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and
timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in
disease progression or disability. With the emergence of structurerelated outcome measures as the primary means for
assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring
and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in
erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life.
Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported
from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in
maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and
radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.
Keywords: etanercept, infliximab, rheumatoid
arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic, systemic,
inflammatory disease that affects approximately 1% of
the world’s population. It is characterized by a loss in
functional capacity resulting from decreased structural
integrity of the joints, diminished muscle strength and
tone, and a variety of psychosocial factors. A 10-year
outcomes study of 183 patients with early RA showed
that most (94%) are able to manage daily life activities.
On the basis of disability scores on the Health
Assessment Questionnaire (HAQ), a self-reported
measure of functional impairment, 20% of patients had
no disability, 28% were mildly disabled, and 10% were
seriously disabled [1].
Treatment strategies have traditionally involved the
use of disease-modifying antirheumatic agents
(DMARDs) and,
S24
more recently, the tumor necrosis factor (TNF)
antagonists. To optimize the functional outcomes of
patients with RA, it is essential to examine the role of
these newer agents in preventing disease progression
and, potentially, in producing a cure. This examination
requires several considerations, including (1) the
importance of treating patients early, (2) the fact that
improvements in symptom control do not necessarily
signal reduced disease progression and disability, (3)
the emergence of structurerelated parameters as a
primary means of assessing response to therapy, (4)
therapeutic alternatives for patients who do not
respond satisfactorily to one anti-TNF agent, and (5)
discontinuation rates and whether they influence
therapy, given the desire for durable clinical
responses.
ACR = American College of Rheumatology; AE = adverse event; ATTRACT = Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with
Concomitant Therapy; CI = confidence interval; DMARDs = disease-modifying antirheumatic drugs; ERA = Early Rheumatoid Arthritis; ESR =
erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; NSAID = non-steroidal anti-inflammatory drug; RA = rheumatoid
arthritis; TNF = tumor necrosis factor.
*
*
Delayed
treatment
Early
treatment
Available online http://arthritis-research.com/content/6/S2/S24
Table 1
Figure 1
12
14
Improved symptom control with disease progression
8
10
Score
Parameter Year 1 Year 2 Year 3 Outcome
4 6
0 2
0 6 12 18 24
Months
Study of delayed and early treatment on disease outcome in patients
with recent-onset rheumatoid arthritis (RA). *P<0.05 compared with
the delayed-treatment group. Adapted, with permission, from
Excerpta Medica [2].
The importance of treating patients early
more timely use of DMARDs [4] and biologic therapy
[5,6]. A panel of rheumatic disease experts has issued
a consensus report addressing the role of TNF
antagonists in patients with RA; the panel stated that
TNF antagonists may become first-line agents in the
treatment of RA and should not be reserved for
patients with advanced disease [6].
Improvements in symptom control do not
necessarily signal reduced disease
progression and disability
A study by Wolfe investigated the relationship between
HAQ disability scores and the clinical course of RA in
One nonrandomized, comparative study of pre-biologic
1843 patients [7]. Analysis of 1-year, 2-year, and
therapies (namely standard DMARDs) compared the
3-year
effects of delayed and early treatment on disease
outcome in 206 patients with probable or definite
recentonset RA as defined by the 1958 and 1987
American College of Rheumatology (ACR) criteria,
respectively [2,3]. The delayed treatment group (n=109)
received nonsteroidal anti-inflammatory drugs (NSAIDs)
followed by the administration of standard DMARDs –
chloroquine or salazopyrine – at a mean of 123 days
after diagnosis. The early treatment group (n=97)
received NSAIDs with standard DMARDs at a mean of
15 days after the diagnosis (Fig.1) [2]. Results at 2 years
indicated less radiographically evident joint destruction
in the early-treatment group than in the
delayed-treatment group (median Sharp scores: 3.5
versus 10; P<0.05). Thus, even with non-biologic
therapies, a delay in therapy resulted in poorer
outcomes.
The advantages of the early initiation of therapy
combined with the introduction of newer antirheumatic
agents (such as the TNF biologic response modifiers)
have shifted treatment models toward the earlier and
Mean
SJC
5.2
3.5
2.4
Redu
ced
sympt
oms
Mean
TJC
13.7
9.0
6.5
Redu
ced
sympt
oms
Mean
pain
22.4
13.4
11.1
Redu
ced
sympt
oms
Mean
Larse
n 5.6
12.3
16.9
Incre
ased
struct
ural
ind
ex
da
ma
ge
SJC,
swoll
en
joint
count (maximum score 44); TJC, tender joint count (maximum score
53). Data on file, Centocor, Inc., Malvern, PA, USA.
Sharp score
data from this study indicates that HAQ disability scores
might increase gradually with significant increases in
structural damage, as assessed by Larsen index scores
(data on file, Centocor, Inc., Malvern, PA, USA) (Table
1).
There might also be a discrepancy between disease
course and the presence of clinical indicators of disease
such as pain, swollen joint count, and tender joint count.
Wolfe and Sharp compared clinical disease assessment
and radiographic progression in 256 patients with RA
who were seen within 2 years of disease onset and were
followed for up to 19 years [8]. On the basis of Sharp
scores, joint-space narrowing, and erosion scores, it
was concluded that RA progresses at a constant, linear
rate that is neither greater in early RA nor reduced later
in the course of disease (Fig.2), and that other factors
(such as mean erythrocyte sedimentation rate [ESR],
mean grip strength, rheumatoid factor positivity, and
swollen joint count) serve as independent predictors of
radiographically evident joint destruction [8].
The emergence of structure-related
parameters as a primary means of assessing
response to therapy
The 2002 ACR Guidelines for the management of
rheumatoid arthritis state that the ultimate goals of RA
management are the prevention or control of joint
damage, the prevention of loss of function, and the
amelioration of pain [5]. Kirwan described a potential
pathogenic pathway for RA that supports these
principles, showing a possible correlation between
clinical symptoms and X-ray changes in RA (Fig.3) [9].
As assessment of structural damage in RA is
emerging as an important method of evaluating
disease outcomes, radiographs (that is, X-rays), have
become essential tools not just for the diagnosis of RA
but for continued monitoring. Radiographic findings
can be reported with the Sharp score or the Larsen
index. The total Sharp score is derived from the
combination of erosion and joint-space narrowing
S25
Arthritis Research & Therapy
Vol 6 Suppl 2 Yocum
Initiating
eventInitiat
ing event
Figure 3
Sharp score JSN score JE score
Figure 2
100
80
Structural
damage
progressi on
Synovitis
PannusSynovitis
Pannus
60
4
0
Pain andClinica
stiffne l
ssPain symptom
and
s
stiffne
ss
2
0
0
0
Disease duration
(years)
5
0
5
0
1
1
2
1 2X-ray
changes
Figure 4
Change in Sharp scores, joint-space narrowing (JSN), and joint
erosion (JE) scores showing that rheumatoid arthritis progresses at
a constant, linear rate. Adapted, with permission, from John Wiley &
Sons, Inc. [8].
5
Swellin
gSwelli
ng
Joint-spa
ce
narrowing
Joint-spa
ce
narrowing
Joint
erosio
nsJoin
t
erosio
ns
Potential pathogenic pathway for rheumatoid arthritis, supporting–0.
5 a
relationship between structural damage and clinical symptoms.
Adapted, with permission, from Excerpta Medica [9].
4.00.0 0.50.5
4
3
2
1
0
–1
scores. Joint-space narrowing is not a major
contributor to the overall Larsen index score [10].
–2
P value vs MTX
<0.001
The Early Rheumatoid Arthritis (ERA) trial compared
the efficacy of etanercept and methotrexate in 632
patients with early RA [14,15]. This trial consisted of a
1-year blinded phase [14] and a 1-year open-label
extension phase [15]. Results at 2 years showed a
significantly decreased incidence of structural joint
disease in the etanercept-treated patients, as
determined by changes in Sharp score (P=0.001) and
erosion score (P=0.001); however, there was no
statistically significant difference in joint-space
narrowing scores (Fig.5) [15]. These two trials show
how TNF antagonists have raised the standard of
treating patients with RA on the basis of their shown
ability to produce significant improvements in clinical
parameters (such as ACR response) and to retard the
radiographically assessed progression of joint damage.
<0.001
<0.001
<0.001
Data from the ATTRACT (Anti-Tumor Necrosis Factor Trial in
Rheumatoid Arthritis With Concomitant Therapy) study showing
the superiority of infliximab plus methotrexate (MTX) over
methotrexate alone, as determined by the median change in the
modified Sharp score. Data from [12].
Both Sharp and Larsen scores have been used to report
outcome assessment data in clinical trials of TNF
antagonists. The Anti-Tumor Necrosis Factor Trial in
Rheumatoid Arthritis With Concomitant Therapy
(ATTRACT) was a 2-year, double-blind,
placebo-controlled study that showed that the TNF
antagonist infliximab, in combination with methotrexate,
was superior to methotrexate alone in improving the
radiographic outcomes of patients with RA [11–13]. At
the 52-week endpoint, the infliximab-treated patients
showed improvements in erosion, joint-space narrowing,
and Sharp scores (Fig.4) [12].
S26
Although radiographic evidence of disease
progression is frequently assessed by Sharp scores,
clinical data are usually assessed by ACR criteria,
such as the ACR20. Achievement of an ACR20
response indicates a greater
MTX +
placebo (n
= 63)
3 mg/kg q 8
wk
3 mg/kg q 4
wk
10 mg/kg q 8
wk
(n = 71)
(n = 71)
(n = 77)
10 mg/kg q 4
wk
(n = 66)
than 20% improvement in tender and swollen joint
counts and at least three of the following disease
activity variables: the patient’s assessment of pain,
the patient’s global assessment of disease activity, the
physician’s global assessment of disease activity, the
patient’s assessment of physical function, and the
ESR or the C-reactive protein level [5,16]. However,
failure to achieve an ACR20 response should not
necessarily be interpreted as a failure of therapy.
Preliminary subgroup analysis data from the
ATTRACT study indicate that in patients who failed to
achieve an ACR20 response (that is,
non-responders), those treated with infliximab and
methotrexate showed a greater improvement in
ACR20 response than the patients treated with
methotrexate alone (Fig.6) (data on file, Centocor,
Inc.). Thus, the regular use of
Methotrexate
20 mg
Etanercept 25
mg
Figu
re 5
Available online http://arthritis-research.com/content/6/S2/S24
Figure 6
ACR 20 Responders ACR 20 Non-Responders
*
**
n =34 *N=40 N=25 N=31 n =38 n =10n
=33 n =32 n =38 n =28n =40 n =25 n =31
3.5
3.2
-1.7 -2.0* *
5.0
3.6
1.9
3.0
1.3
0.7* 0.7
2.5
2.0
1.5
4.3
4.0
1
.
2
2.5
1.3
0.5*
3.0
0.5
2.0
1.3*
0.0
1.0
1.0
0.0
0.5
0.
0
* P =
0.001
1
.
2
-1
.0
Total
Sharp
score
Joint erosion Joint-space
narrowi ng
Data from the ERA (Early Rheumatoid Arthritis) trial showing the
superiority of etanercept over methotrexate, as determined by
improvements in erosion and Sharp scores, but not joint-space
narrowing score at 2 years. Adapted, with permission, from John
Wiley & Sons, Inc. [15].
radiographic imaging, including X-rays, can be
considered an important component of the overall
assessment and evaluation of patients with RA.
Therapeutic alternatives for patients who do
not respond satisfactorily to one anti-TNF
agent
The failure of a patient to respond to a single TNF
antagonist should not be taken to mean that the patient
is refractory to all TNF antagonists. Studies have shown
success with infliximab in patients who have failed to
respond to etanercept therapy, and vice versa. In one
study, investigators in community rheumatology
practices documented the efficacy and safety of
infliximab in patients with an inadequate response to
etanercept [17]. After four infusions of infliximab,
patients experienced reductions in mean tender joint
counts (57%), mean swollen joint counts (66%), ESR
(20%), and mean daily prednisone requirement (38%)
Methotrexate alone Infliximab 3
mg/kg q 8 wk + methotrexate
Infliximab 3 mg/kg q 4 wk +
methotrexate Infliximab 10
mg/kg q 8 wk + methotrexate
Infliximab 10 mg/kg q 4 wk +
methotrexate
(Table 2) [17]. Although this study lacks the structure of
a randomized controlled clinical trial, it provides
preliminary data that TNF antagonist therapy should not
be abandoned in the face of an apparent initial
unsatisfactory response.
Do discontinuation rates influence therapy?
Discontinuation rates of a pharmacologic agent,
including antirheumatic agents, can influence therapy.
Discontinuation rates can serve as a reasonable guide to
the efficacy or safety of an agent. Before definitive
conclusions can be made, other variables should be
considered, for example the phase of therapy (such as
acute, continuation, maintenance), reasons for the
discontinuation (such as lack of efficacy, toxicity, adverse
events [AEs]), associated symptoms or intercurrent
illness, and drug profile (including
Prelim
inary
radiog
raphic
data
from
the
ATTR
ACT
(Anti-T
umor
Necro
sis
Factor
Trial in
Rheu
matoid
Arthriti
s With
Conco
mitant
Thera
py)
study,
indicat
ing the
superi
ority of
inflixi
mab
plus
metho
Table 2
Clinical changes after a switch from etanercept to infliximab
Post-infliximab
Pre-infliximab (4 doses;
Parameter (baseline) week 14) Outcome
Mean tender joints (n) 17.1 7.3 57% reduction Mean swollen joints (n)
11.2 3.8 66% reduction ESR (mm/h) 33 26.5 20% reduction Mean
prednisone dosage 9.2 5.7 38% reduction
(mg/day)
ESR, erythrocyte sedimentation rate. Data from [17].
previous medications and concomitant therapy).
Discontinuation rates can also serve as a reflection of the
chronic, aggressive course of the disease, which can
require more than one therapy or can sometimes involve
the switching of agents to achieve satisfactory clinical
outcomes.
For a better understanding of how discontinuation
rates affect therapy in the era of anti-TNF agents, a
review of the discontinuation rates with DMARDs
based on three large studies is presented [18–20].
According to a Markov model based on the Arthritis,
Rheumatism, and Aging
Median change from baseline
(Sharp scores)
Change in Sharp scores/2 years
trexate over methotrexate alone in patients who did and did not
S27
achieve an ACR20 (that is, ACR20 responders and non-responders).
ACR20 is a more than 20% improvement in tender and swollen joint
counts and at least three of the following disease activity variables: the
patient’s assessment of pain, the patient’s global assessment of
disease activity, the physician’s global assessment of disease activity,
the patient’s assessment of physical function, and the erythrocyte
sedimentation rate or C-reactive protein level. *P<0.05 versus placebo.
Data on file, Centocor, Inc., Malvern, PA, USA.
Arthritis Research & Therapy
Vol 6 Suppl 2 Yocum
Table 3
Discontinuation rates at 1 year for anti-TNF agents in randomized clinical trials
No. of Trial patients Patient characteristics Regimens Discontinuation rates (%)
ATTRACT [12] 428 Active RA despite methotrexate therapy; Infliximaba21 mean duration 9–12 years 3 mg q 4 weeks
a3 mg q 8 weeks 10 mg q 4 weeks 10 mg q 8 weeks Placebo(weekly) 50 ERA [14] 632 Early RA; Etanercept
mean duration <1 year (i.e. 11–12 months) 25 mg twice weekly 15 Methotrexate (mean, 19 mg) weekly 21
aAll groups also received methotrexate, mean 16–17 mg/week. ATTRACT, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With
Concomitant Therapy; ERA, Early Rheumatoid Arthritis.
S28
Medical Information System (ARAMIS) postmarketing
surveillance cohort (n=4285 consecutively enrolled
patients with RA who were followed up for 17,085
patient-years), 46–60% of patients initially receiving
methotrexate alone would still be on methotrexate alone
or with a DMARD after 5 years [20]. When patterns of
drug use in patients with RA in a community setting
were evaluated, drug discontinuation and medication
switching were observed to be common [19]. Almost
20% (1300 of 6944) of patients who took at least one
antirheumatic drug during the study year used a
DMARD, with methotrexate being the most frequently
used. Of the DMARD users, 23% discontinued the drug
during the study year, 19% were taking other concurrent
DMARDs, and 16% added another DMARD. DMARDs
were often used with other (that is, non-DMARD)
agents, because 63% of DMARD users were also taking
an NSAID and 61% were taking a corticosteroid [19].
Aletaha and Smolen [18] evaluated the treatment
patterns with traditional DMARDs and their changes
during the two decades before the introduction of newer
antirheumatic agents. The study involved 593 patients
with RA who were followed from their first presentation
in the clinic throughout the course of their disease, of
whom 222 patients received their first DMARD during
the study [18]. Before 1985 most (65–90%) of initial
DMARDs were gold compounds, whereas after 1985
methotrexate was the initial DMARD in 29% of new
patients. Patients with high disease activity were more
likely to be receiving methotrexate than other DMARDs,
and first DMARDs in new patients were used for longer
than subsequent DMARDs, because they were more
effective [18]. On the basis of an analysis of 122
controlled trials and observational studies involving
16,071 patients with RA, Hawley and Wolfe [21]
concluded that good retention rates in studies lasting
3–12 months were not representative of long-term
results, although the retention rates observed in
controlled and observational studies were similar during
the first treatment year.
Discontinuation rates for anti-TNF agents as observed
in two long-term, randomized RA trials, one involving
infliximab (ATTRACT) and the other etanercept
(ERA), are listed in Table 3 [12,14]. These trials
differed in terms of study size (428 versus 632
patients), stage of RA (laterstage [active] versus
early), and regimens (anti-TNF therapy plus a
DMARD compared with placebo plus a DMARD
[ATTRACT], versus anti-TNF monotherapy compared
with a DMARD [ERA]). In the ATTRACT study, in
which patients were randomized to receive 3 or 10mg
of infliximab every 4 or 8 weeks, or placebo, with
methotrexate given to all groups, 54-week data
showed that discontinuation rates due to AEs were
about 8% (26 of 340) in infliximab-treated patients
compared with about 16% (7 of 44) of patients in the
placebo-plus-methotrexate group [12]. The
discontinuation rates due to lack of efficacy were
about 12% (40 of 340) in the infliximab-treated
patients compared with about 73% (32 of 44) in the
placebo-plus-methotrexate group. In the ERA trial, in
which patients were randomized to receive 10 or
25mg of etanercept twice weekly, or methotrexate
weekly, discontinuation rates due to AEs or elevated
aminotransferase levels were 6% for the group
receiving 10mg of etanercept, 5% for the group
receiving 25mg of etanercept (P<0.001 versus
methotrexate), and 11% for the methotrexate group
[14]. Lack of efficacy was the reason for
discontinuation in 7% and 5% of patients in the
groups receiving 10 and 25mg of etanercept,
respectively, versus 4% in the methotrexate group
[14].
The chronic course of RA merits long-term
maintenance therapy. Efforts to lower discontinuation
rates have included the administration of methotrexate
together with anti-TNF agents. Support for enhanced
therapeutic efficacy with this approach has been
documented [22,23]. Maini and colleagues conducted
a 26-week, double-blind, placebo-controlled trial in
101 patients with active RA exhibiting an incomplete
response to methotrexate (about
9–15 mg per week for the last 3 months before the
study) [22]. Patients received either infliximab 1, 3, or
10mg/kg intravenously with or without methotrexate
7.5mg per week, or placebo plus methotrexate 7.5mg
per week intravenously at weeks 0, 2, 6, 10, and 14;
follow-up continued until week 26 [22]. Results showed
that when infliximab (at all dose regimens in the study)
was administered together with infliximab and weekly
methotrexate, 60–80% of patients attained a Paulus
20% response for up to 14 weeks, and 50–60% of
patients sustained a response after the cessation of
treatment until the end of the study [22]. In the
ATTRACT study, the combination of infliximab and
methotrexate over 30, 54, and 102 weeks provided
significant, clinically relevant improvement in a majority
of patients with RA who had an incomplete response to
methotrexate alone; however, discontinuation rate data
at 102 weeks have yet to be made available [11–13]. As
more data from long-term trials that involve these agents
accumulate, focusing on discontinuation rates and
correlating safety and efficacy parameters, the role of
concomitant methotrexate in the long-term maintenance
of anti-TNF therapy will be clarified further.
Aside from clinical trial data, clinical practice data
report the discontinuation rates of anti-TNF agents.
A 2-year Swedish study conducted in seven clinical
centers evaluated the anti-TNF agents infliximab
(n=135) and etanercept (n=166]) and a
newer-generation DMARD, leflunomide (n=103), for
efficacy (based on ACR response criteria) and
tolerability (based on survival and AEs) in patients
with RA [24]. Initial doses of the agents in this study
were 3mg/kg intravenously at weeks 0, 2, 6, and 12
and every 8 weeks thereafter for infliximab, and
25mg subcutaneously twice weekly for etanercept;
appropriate dose adjustments and switching to
another of the three agents were allowed after
withdrawal from one treatment [24]. On the basis of
ACR20 and ACR50 responses, the TNF
antagonists performed significantly better than the
newer DMARD, and no significant differences were
noted between the efficacy of infliximab and
etanercept at 0.5, 1.5, 9, and 12 months [24]. At 3
months, ACR20 and ACR50 responses were noted
in a greater percentage of patients who received
infliximab than leflunomide (P<0.01 and P<0.05,
respectively), whereas ACR20 and ACR50
responses were noted in a greater percentage of
etanercept-treated and leflunomidetreated patients
at 3 months (P<0.001) and 6 months (P<0.05) [24].
Survival data showed that 75%, 79%, and 22% of
A
v
a
i
l
a
b
l
e
patients continued to receive infliximab, etanercept,
and leflunomide, respectively, after 20 months (for
24-month discontinuation rates of 25%, 21%, and
78%, respectively) [24]. In the infliximab-treated
and etanercepttreated patients in this study, AEs
were the primary cause of drug discontinuation.
There were 2.8 life-threatening AEs per 100
treatment-years (namely anaphylactoid reaction,
mesothelioma, and severe pharyngitis) and 10.0
o
n
l
i
n
e
h
t
t
p
:
/
/
a
r
t
h
r
i
t
i
s
r
e
s
e
a
r
c
h
.
c
o
m
/
c
o
n
t
e
n
t
/
6
/
S
2
/
S
2
4
serio
us AEs per 100 treatment-years (namely allergic
reactions, bacterial infections, Hodgkin’s/non-Hodgkin’s
lymphoma, thrombocytopenia, lupus-like reaction,
discoid lupus) with infliximab. Etanercept-treated
patients experienced 1.3 fatal AEs per 100
treatment-years (namely gastroenteritis, immunocytoma
of the breast, and myocardial infarction) and 7.0 serious
AEs per 100 treatment-years (namely myocardial
infarction, bacterial infections, uterine cervical
carcinoma, leukemia, malaise, leucopenia, Bell’s
paralysis, cutaneous vasculitis, discoid lupus) [24].
An electronic medical record system was used to review
all patients seen in a university rheumatology clinic (the
Arizona Arthritis Center at the University of Arizona) who
had been treated with infliximab (n=118) or etanercept
(n=90) between February 1998 and May 2002 [25]. Data
were collected on diagnosis, disease duration, dates of
therapy, reasons for treatment discontinuation, and AEs
and serious AEs. Most (82%) of the 208 patients in this
study had a diagnosis of RA [25]. Kaplan–Meier analysis
for the discontinuation of any anti-TNF therapy showed
a mean medication duration of 768 days (95%
confidence interval [CI] 693–843 days) with a maximum
follow-up time of 1260 days [25].
For infliximab, the mean time to discontinuation was 931
days (95% CI 844–1018 days), with 32 (27%) of 118
patients discontinuing infliximab. After 15 months there
was a 0% rate of discontinuation with infliximab [25]. For
etanercept, the mean time to discontinuation was 595
days (95% CI 491–700 days), with 58 (64%) of 90
patients discontinuing etanercept [25]. The log-rank test
coefficient for the difference between survival curves for
the two groups was 20.03 (P<0.01) and the
Gehan–Breslow coefficient was 16.01 (P<0.001) [25].
The investigators documented a low probability of
discontinuations of infliximab after 1 year of treatment
and concluded that, on the basis of the results of the
survival analysis of the data from their practice, patients
receiving infliximab remain on therapy significantly
longer than those on etanercept [25].
Conclusion
Clinical trials and community findings support the
efficacy and safety of the current TNF antagonists. To
optimize comprehensive therapeutic outcomes in
clinical practice, DMARDs or anti-TNF agents, or both,
should be instituted early, and patient status and
response to therapy should be monitored on a regular
basis by using X-rays and radiographic scores.
Structure-related parameters are emerging as a most
important measure of outcome by which the efficacy
of antirheumatic therapies are evaluated. In addition
to a reduction of symptoms and improvement in
physical function, optimal reductions in erosions and
joint-space narrowing should be part of the goals of
therapy. Patients who show an unsatisfactory
response to
S29
S30
Arthritis Research & Therapy
Vol 6 Suppl 2 Yocum
one anti-TNF agent should be started on another.
Adherence to therapy is an important element in
optimizing outcomes, and durability of therapy can also
be achieved in the clinical setting. Finally, the
concomitant administration of methotrexate might be
important in the maintenance of TNF antagonist therapy
in the long term. Overall, the TNF antagonists have
provided significant improvements in clinical and
radiographic outcomes for patients with RA, especially
those who have had an incomplete response to
methotrexate therapy.
Competing interests
DY is, or has been, a speaker for Centocor,
BoehringerIngelheim and Amgen, is a consultant for
Centocor, Novartis and Boehringer-Ingelheim, and has
received grants from Centocor, Amgen, Abbott,
Medimmune, Alexion and Novartis.
Acknowledgement
The transcript of the World Class Debate for ACR 2002 has been
published electronically in Joint and Bone. This article, and others
published in this supplement, serve as a summary of the proceedings
as well as a summary of other supportive, poignant research findings
(not included in the World Class Debate ACR 2002).
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Correspondence
David Yocum MD, Professor of Medicine, Director, Arizona Arthritis
Center, University of Arizona, Health Sciences Center, Tucson, AZ
85724, USA. Tel: +1 520 626 6399; fax: +1 520 626 5018; e-mail:
yocum@u.arizona.edu